ADMET and DMPK最新文献

Background and purpose: Physiologically-based biopharmaceutics modeling (PBBM) has been widely used to predict the oral absorption of drugs. However, the prediction of food effects on oral drug absorption is still challenging, especially for negative food effects. Marked negative food effects have been reported in most cases of quaternary ammonium compounds (QAC). However, the mechanism has remained unclear. The purpose of the present study was to investigate the bile micelle and food binding of QACs as a mechanism of the negative food effect.

Experimental approach: Trospium (TRS), propantheline (PPT), and ambenonium (AMB) were selected as model QAC drugs. The oral absorption of these QACs has been reported to be reduced by 77% (TRS), > 66% (PPT), and 79% (AMB), when taken with food. The fasted and fed state simulated intestinal fluids (FaSSIF and FeSSIF, containing 3 and 15 mM taurocholic acid, respectively) with or without FDA breakfast homogenate (BFH) were used as the simulated intestinal fluid. The unbound fraction (f_u) of the QACs in these media was measured by dynamic dialysis.

Key results: The f_u ratios (FeSSIF/ FaSSIF) were 0.67 (TRS), 0.47 (PPT), and 0.76 (AMB). When BFH was added to FeSSIF, it was reduced to 0.39 (TRS), 0.28 (PPT), and 0.59 (AMB).

Conclusion: These results suggested that bile micelle and food binding play an important role in the negative food effect on the oral absorption of QACs.

Yalkowsky's General Solubility Equation (GSE), with its three fixed constants, is popular and easy to apply, but is not very accurate for polar, zwitterionic, or flexible molecules. This review examines the findings of a series of studies, where we have sought to come up with a better prediction model, by comparing the performances of the GSE to Abraham's Solvation Equation (ABSOLV), and Random Forest regression (RFR) machine-learning (ML) method. Large, well-curated aqueous intrinsic solubility databases are available. However, drugs may be sparsely distributed in chemical space, concentrated in clusters. Even a large database might overlook some regions. Test compounds from under-represented portions of space may be poorly predicted, as might be the case with the 'loose' set of 32 drugs in the Second Solubility Challenge (2020). There appears to be still a need for better coverage of drug space. Increasingly, current trends in predictions of solubility use calculated input descriptors, which may be an advantage for exploring properties of molecules yet to be synthesized. The risk may be that overall prediction approaches might be based on accumulated uncertainty. The increasing use of ML/AI methods can lead to accurate predictions, but such predictions may not readily suggest the strategies to pursue in selecting yet-to-be-synthesized compounds. Based on our latest findings, we recommend predictions based on both 'grouped' ABSOLV(GRP) and 'Flexible Acceptor' GSE(Φ,B) models with the provided best-fit parameters, where Φ is the Kier molecular flexibility index and B is the Abraham H-bond acceptor strength. For molecules with Φ < 11, the prudent choice is to pick the Consensus Model, the average of ABSOLV(GRP) and GSE(Φ,B). For more flexible molecules, GSE(Φ,B) is recommended.

Background and purpose: Flavonoids are a group of phytochemicals found abundantly in various plants. Scientific evidence has revealed that flavonoids display potential biological activities, including their ability to alleviate inflammation. This activity is closely related to their action in blocking the inflammatory cascade and inhibiting the production of pro-inflammatory factors. However, as flavonoids typically have poor bioavailability and pharmacokinetic profile, it is quite challenging to establish these compounds as a drug. Nevertheless, progressive advancements in drug delivery systems, particularly in nanotechnology, have shown promising approaches to overcome such challenges.

Review approach: This narrative review provides an overview of scientific knowledge about the mechanism of action of flavonoids in the mitigation of inflammatory reaction prior to delivering a comprehensive discussion about the opportunity of the nanotechnology-based delivery system in the preparation of the flavonoid-based drug.

Key results: Various studies conducted in silico, in vitro, in vivo, and clinical trials have deciphered that the anti-inflammatory activities of flavonoids are closely linked to their ability to modulate various biochemical mediators, enzymes, and signalling pathways involved in the inflammatory processes. This compound could be encapsulated in nanotechnology platforms to increase the solubility, bioavailability, and pharmacological activity of flavonoids as well as reduce the toxic effects of these compounds.

Conclusion: In Summary, we conclude that flavonoids and their derivates have given promising results in their development as new anti-inflammatory drug candidates, especially if they formulate in nanoparticles.

Background and purpose: Sensitive analytical determination of folic acid is important in clinical laboratories due to its versatile biological functions.

Experimental approach: A simple folic acid sensor was successfully fabricated based on two-dimensional transition metal dichalcogenide MoS₂ modified carbon ionic liquid paste electrode (MoS₂-CILPE). The electrochemical properties of the fabricated electrode were investigated by cyclic voltammetry (CV), differential pulse voltammetry (DPV), and chronoamperometry.

Key results: The fabricated sensor displayed excellent electroactivity towards folic acid using CV. Under optimal conditions (0.1 M PBS (pH 7.0)), the DPV oxidation peak current was proportional to folic acid concentration in the range from 5.0 μM to 100.0 μM with an estimated limit of detection of 1.0 μM and limit of quantification of 5.0 μM.

Conclusion: The ability of the sensor for routine analyses was demonstrated by the detection of folic acid present in folic acid tablets and urine samples with appreciable recovery values.

Background and purpose: Physicochemical properties of an amorphous solid dispersion (ASD) comprising an experimental grade of hydroxypropyl methylcellulose acetate succinate (HPMCAS-MX) with lower glass transition temperature have been previously investigated. This study aimed to evaluate applicability of HPMCAS-MX to hot-melt extrusion (HME) and dissolution-permeation performance of prepared ASDs using MicroFLUX.

Review approach: A physical mixture of indomethacin (IMC) and HPMCAS-MX or -MG (a commercial grade with higher transition temperature) at 20:80 weight ratio was hot-melt extruded to prepare an ASD (IMC-MX and IMC-MG, respectively). The dissolution-permeation performance and the stability of the ASDs were measured.

Key results: A torque reduction at 120 °C implied that IMC-MX transformed into an amorphous state at this temperature, but IMC-MG required around 170 °C. This result was supported by Raman mapping of the the HME samples. IMC-MG and IMC-MX remained in an amorphous state at 40 °C for three months. The initial dissolution rate and solubility of the ASDs were higher than that of crystalline IMC. The apparent permeability of IMC from IMC-MX and IMC-MG was comparable but was approximately two-fold higher than that from crystalline IMC.

Conclusion: HPMCAS-MX enabled HME process at a lower temperature and improved the dissolution-permeation performance of indomethacin.

Background and purpose: The utilization of doxorubicin (DOX) in clinal trials is also challenging owing to its adverse effects, including low oral bioavailability, generation of reactive oxygen species (ROS), cardiotoxicity, and epithelial barrier damage. Recently, scavenging of ROS reduced the cytotoxicity of DOX, suggesting a new approach for using DOX as an anticancer treatment. Thus, in this study, non-silica and silica redox nanoparticles (denoted as RNP^N and siRNP, respectively) with ROS scavenging features have been designed to encapsulate DOX and reduce its cytotoxicity.

Experimental approach: DOX-loaded RNP^N (DOX@RNP^N) and DOX-loaded siRNP (DOX@siRNP) were prepared by co-dissolving DOX with RNP^N and siRNP, respectively. The size and stability of nanoparticles were characterized by the dynamic light scattering system. Additionally, encapsulation efficiency, loading capacity, and release profile of DOX@RNP^N and DOX@siRNP were identified by measuring the absorbance of DOX. Finally, the cytotoxicity of DOX@RNP^N and DOX@siRNP against normal murine fibroblast cells (L929), human hepatocellular carcinoma cells (HepG2), and human breast cancer cells (MCF-7) were also investigated.

Key results: The obtained result showed that RNP^N exhibited a pH-sensitive character while silanol moieties improved the stability of siRNP in physiological conditions. DOX@RNP^N and DOX@siRNP were formed at several tens of nanometers in diameter with narrow distribution. Moreover, DOX@siRNP stabilized under different pH buffers, especially gastric pH, and improved encapsulation of DOX owing to the addition of silanol groups. DOX@RNP^N and DOX@siRNP maintained anticancer activity of DOX against HepG2, and MCF-7 cells, while their cytotoxicity on L929 cells was significantly reduced compared to free DOX treatment.

Conclusion: DOX@RNP^N and DOX@siRNP could effectively suppress the adverse effect of DOX, suggesting the potential to become promising nanomedicines for cancer treatments.

Background and purpose: The widely-used and practically insoluble diprotic acidic dye, bromothymol blue (BTB), is a neutral molecule in strongly acidic aqueous solutions. The Schill (1964) extensive solubility-pH measurement of bromothymol blue in 0.1 and 1.0 M NaCl solutions, with pH adjusted with HCl from 0.0 to 5.4, featured several unusual findings. The data suggest that the difference in solubility of the neutral-form molecule in 1M NaCl is more than 0.7 log unit lower than the solubility in pure water. This could be considered as uncharacteristically high for a salting-out effect. Also, the study reported two apparent values of pK_a1, 1.48 and 1.00, in 0.1 M and 1.0 M NaCl solutions, respectively. The only other measured value found for pK_a1 in the literature is -0.66 (Gupta and Cadwallader, 1968).

Experimental approach: It was reasoned that the there can be only a single pK_a1 for BTB. Also, it was hypothesized that salting-out alone might not account for such a large difference in solubility observed at the two levels of salt. A generalized mass action approach incorporating activity corrections for charged species using the Stokes-Robinson hydration equation and for neutral species using the Setschenow equation, was selected to analyze the Schill solubility-pH data to seek a rationalization of these unusual results.

Key results: BTB reveals complex speciation chemistry in saturated aqueous solutions which had been poorly understood for many years. The appearance of two different values of pK_a1 at different levels of NaCl and the anomalously high value of the empirical salting-out constant could be rationalized to normal values by invoking the formation of a very stable neutral dimer (log K₂ = 10.0 ± 0.1 M^-1). A 'normal' salting-out constant, 0.25 M^-1 was then derived. It was also possible to estimate the 'self-interaction' constant. The data analysis in the present study critically depended on the pK_a1 = -0.66 reported by Gupta and Cadwallader.

Conclusion: A more reasonable salting-out constant and a consistent single value for pK_a1 have been determined by considering a self-interacting (aggregation) model involving an uncharged form of the molecule, which is likely a zwitterion, as suggested by literature spectrophotometric studies.

Reliable, rapid, highly selective and sensitive analytical methods for the determination of antineoplastic agent 5-fluorouracil (5-FU) in human body fluids (blood serum/plasma and urine) are required to improve the chemotherapy regimen to reduce its toxicity and improve efficacy. Nowadays, electrochemical techniques provide a powerful analytical tool for 5-FU detection systems. This comprehensive review covers the advances in the development of electrochemical sensors for the quantitative determination of 5-FU, mainly focused on original studies reported from 2015 to date. We have summarized recent trends in the electrochemical sensor systems applied for the analysis of 5-FU in pharmaceutical formulations and biological samples, and critically evaluated the key performance metrics of these sensors (limit of detection, linear range, stability and recovery). Challenges and future outlooks in this field have also been discussed.

A simple and sensitive method for the determination of propranolol using a modified carbon paste electrode with graphene/Co₃O₄ nanocomposite was presented. The electrochemical measurements of propranolol are studied using differential pulse voltammetry, cyclic voltammetry and chronoamperometry. The graphene/Co₃O₄ nanocomposite exhibits excellent catalytic activity towards the electrochemical oxidation of propranolol in phosphate buffer solution of pH 7.0. The graphene/Co₃O₄ nanocomposite facilitates the determination of propranolol in the concentration range 1.0-300.0 μM and a detection limit and sensitivity of 0.3 μM. and 0.1275 μA/μM were achieved.